Neuronal inhibition of the autophagy nucleation complex extends life span in post-reproductive C. elegans.

Autophagy is a ubiquitous catabolic process that causes cellular bulk degradation of cytoplasmic components and is generally associated with positive effects on health and longevity. Inactivation of autophagy has been linked with detrimental effects on cells and organisms. The antagonistic pleiotropy theory postulates that some fitness-promoting genes during youth are harmful during aging. On this basis, we examined genes mediating post-reproductive longevity using an RNAi screen. From this screen, we identified 30 novel regulators of post-reproductive longevity, including pha-4 Through downstream analysis of pha-4, we identified that the inactivation of genes governing the early stages of autophagy up until the stage of vesicle nucleation, such as bec-1, strongly extend both life span and health span. Furthermore, our data demonstrate that the improvements in health and longevity are mediated through the neurons, resulting in reduced neurodegeneration and sarcopenia. We propose that autophagy switches from advantageous to harmful in the context of an age-associated dysfunction.

Continuous intraoperative neuromonitoring of the facial nerve predicts postoperative facial palsy in parotid surgery: a prospective study.

PURPOSE: Facial palsy (FP) is the most significant complication of parotidectomy. Currently, the use of intermittent intraoperative neuromonitoring (iIONM) in parotid surgery facilitates nerve detection, which is paramount to nerve protection. Continuous IONM (cIONM), as applied in thyroid surgery, enables real-time information on electrophysiological nerve status through continuous nerve stimulation, thereby allowing consequent amplitude analysis. To date, the application of cIONM in parotid surgery has not been noted in literature. METHODS: We performed parotidectomies with anterograde facial nerve visualization using cIONM in 32 consecutive patients in a prospective study (German Register of clinical studies-DRKS 00011051) during the period October 2016 to January 2020. After the facial trunk had been exposed, an atraumatic stimulation electrode was placed and the nerve was stimulated at 3 Hz, at a low threshold (0.62 ± 0.06 mA), for the entire duration of the preparation. Selected electrophysiological parameters were collected and compared to postoperative facial nerve function, measured by the House-Brackmann grading system. RESULTS: In the post hoc analysis, a significant correlation between a drop in amplitude (< 50% of the "baseline" amplitude) and postoperative FP was recorded (p = 0.001). True positive prediction of FP was noted in 14 out of 16 patients and true negative in 10 out of 16. The sensitivity was 87.5% (AUC 0.75), with a high negative predictive value of 83.3%. CONCLUSION: cIONM has significant value in predicting postoperative FP in parotidectomy. Future development of an acoustic/optic warning system in IONM devices could prevent nerve injury in real time.

Capitalizing on paradoxical activation of the mitogen-activated protein kinase pathway for treatment of Imatinib-resistant mast cell leukemia.

Prevention of fatal side effects during cancer therapy of cancer patients with high-dosed pharmacological inhibitors is to date a major challenge. Moreover, the development of drug resistance poses severe problems for the treatment of patients with leukemia or solid tumors. Particularly drug-mediated dimerization of RAF kinases can be the cause of acquired resistance, also called "paradoxical activation." In the present work we re-analyzed the effects of different tyrosine kinase inhibitors (TKIs) on the proliferation, metabolic activity, and survival of the Imatinib-resistant, KIT V560G, D816V-expressing human mast cell (MC) leukemia (MCL) cell line HMC-1.2. We observed that low concentrations of the TKIs Nilotinib and Ponatinib resulted in enhanced proliferation, suggesting paradoxical activation of the MAPK pathway. Indeed, these TKIs caused BRAF-CRAF dimerization, resulting in ERK1/2 activation. The combination of Ponatinib with the MEK inhibitor Trametinib, at nanomolar concentrations, effectively suppressed HMC-1.2 proliferation, metabolic activity, and induced apoptotic cell death. Effectiveness of this drug combination was recapitulated in the human KIT D816V MC line ROSAKIT D816V and in KIT D816V hematopoietic progenitors obtained from patient-derived induced pluripotent stem cells (iPS cells) and systemic mastocytosis patient samples. In conclusion, mutated KIT-driven Imatinib resistance and possible TKI-induced paradoxical activation can be efficiently overcome by a low concentration Ponatinib and Trametinib co-treatment, potentially reducing the negative side effects associated with MCL therapy.

The pattern of epistaxis recurrence in patients taking prophylactic acetylsalicylic acid (ASA) from a 10 year cohort.

OBJECTIVES: Epistaxis is the most common otolaryngological emergency and one-third of epistaxis patients regularly take low-dose acetylsalicylic acid (ASA) for the prevention of cardiovascular disease (CVD). The shift in contemporary guidelines identifies little benefit of ASA intake in patients who have not previously had an infarction. Existing evidence confirms ASA intake as a factor for severe epistaxis, while the evidence concerning its impact on recurrence is ambiguous. There are no available studies which justify the administration of these drugs nor are there any studies correlating the effects of these drugs to the SCORE2 CVD risk stratifying scale. STUDY DESIGN: A retrospective analysis of all admitted epistaxis patients in a tertiary academic hospital for the 10 year period 2011 to 2021. METHODS: Patient data were analysed using the hospital information software. A recurrence was defined as an epistaxis episode requiring hospital readmittance for at least one night. Patients taking anticoagulants were excluded (N = 421). RESULTS: 444 patients were included: 246 were taking ASA and 198 were not (NoASA). ASA patients had more frequent recurrence in general (p = 0.03), more recurrences per patient (p = 0.002), and more changes in bleeding localisation (p = 0.04). Recurrence in the ASA group was associated with lower haemoglobin values (HR 0.62, p < 0.0001), while surgery (HR 6.83, p < 0.0001) was associated with recurrence in the NoASA group. ASA patients had a statistically significant (r 0.33, p = 0.032) correlation between the total number of epistaxis recurrences and SCORE2. The indication for drug intake was highly questionable in as much as 40% of ASA patients. Follow-up time was 5.27 years. CONCLUSIONS: Epistaxis patients taking prophylactic ASA are significantly more burdened by recurrence, because they have more frequent recurrences, a greater number of recurrences per patient, and more changes in bleeding localisations when compared to control patients. The drug indication is questionable in up to 40% of ASA patients, exposing them unnecessarily to recurrence.

Basal Cell Carcinoma of the Head and Neck-A Retrospective Single-Centre Comparison of the Recurrence Rate after R0 or R1 Resection.

The treatment guidelines for basal cell carcinoma (BCC) postulate complete surgical excision using microscopically controlled resection (MOHS) as the gold standard. The need to obtain a small safety margin in the complex anatomical area of the head and neck is very challenging due to the individual characteristics (localization, histology, and size) of tumors and the fact that the postoperative loss of quality of life depends on the surgical defect size. The R1 status is histopathologically defined when the safety margin is less than 1 mm even if there are no tumor cells actually infiltrating the resection margin. Therefore, some studies have already favored a watch-and-wait-strategy in R1 situations. We aimed to evaluate the outcome and recurrence rate of resected BCCs of the head and neck, especially in a histologically proven R1 situation. The outcomes of all resected BCCs observed during a 5-year period (January 2009-December 2013) in a tertiary care center were analyzed. Our standard operating procedure was microscopically controlled surgical excision with reresections until an R0 situation was achieved. In selected patients, an R1 status has been accepted after at least two resections. From the included 191 BCCs, the R1 status was accepted as the final result in 46 (24.1%) cases which had surgically clear margins and were closely followed-up. From 54 patients in the R0 and 40 patients in the R1 group who completed the follow-up (2.4 ± 0.4 years), we observed 0 and 2 local recurrences, respectively (p = 0.19). In cases where frequent follow-up can be secured and the surgical area is delicate, a surgical closure at R1 status can be justified as the recurrence rate is not significantly higher compared with R0.

Effects of supervised aerobic exercise on cardiorespiratory fitness and patient-reported health outcomes in colorectal cancer patients undergoing adjuvant chemotherapy-a pilot study.

PURPOSE: Colorectal cancer and its treatment are associated with debilitating side effects. Exercise may improve the physical and psychological wellbeing of cancer patients; however, evidence in colorectal cancer patients undergoing adjuvant chemotherapy is limited. This pilot study aimed to explore the effects of supervised aerobic exercise on cardiorespiratory fitness and patient-reported health outcomes in colorectal cancer patients undergoing adjuvant chemotherapy. METHODS: Patients who had undergone curative resection for colorectal cancer (stages II-III) and were scheduled to receive adjuvant chemotherapy were enrolled into this non-randomized controlled trial. Patients in the intervention group (IG) took part in a 6-month supervised aerobic exercise program, while the control group (CG) received usual care. Cardiorespiratory fitness (measured by peak oxygen consumption) was assessed at baseline and 6 months. Fatigue, quality of life, and physical activity levels were additionally assessed at 3 months. RESULTS: In total, 59 patients (33 in IG vs. 26 in CG) were enrolled into this study. Eighteen patients (9 in IG vs. 9 in CG) dropped out of the study prior to the 6-month follow-up. Significant improvements in cardiorespiratory fitness (p = .002) and selected patient-reported health outcomes, such as reduced motivation (p = .015) and mental fatigue (p = .018), were observed in the IG when compared to the CG. CONCLUSION: To our knowledge, this is the first study to investigate the effects of a supervised aerobic exercise program in colorectal cancer patients undergoing adjuvant chemotherapy. The significant and clinically meaningful improvements in CRF warrant further randomized controlled trials to confirm these findings. TRIALS REGISTRATION: German Clinical Trials Register Identifier: DRKS00005793, 11/03/2014, retrospectively registered.

Endoplasmic Reticulum Homeostasis Regulates TLR4 Expression and Signaling in Mast Cells.

The endoplasmic reticulum (ER) is a dynamic organelle that responds to demand in secretory proteins by undergoing expansion. The mechanisms that control the homeostasis of ER size and function involve the activation of the unfolded protein response (UPR). The UPR plays a role in various effector functions of immune cells. Mast cells (MCs) are highly granular tissue-resident cells and key drivers of allergic inflammation. Their diverse secretory functions in response to activation through the high-affinity receptor for IgE (FcεRI) suggest a role for the UPR in their function. Using human cord blood-derived MCs, we found that FcεRI triggering elevated the expression level and induced activation of the UPR transducers IRE1α and PERK, accompanied by expansion of the ER. In mouse bone marrow-derived MCs and peritoneal MCs, the ER underwent a more moderate expansion, and the UPR was not induced following MC activation. The deletion of IRE1α in mouse MCs did not affect proliferation, survival, degranulation, or cytokine stimulation following FcεRI triggering, but it did diminish the surface expression of TLR4 and the consequent response to LPS. A similar phenotype was observed in human MCs using an IRE1α inhibitor. Our data indicate that the ER of MCs, primarily of humans, undergoes a rapid remodeling in response to activation that promotes responses to TLR4. We suggest that IRE1α inhibition can be a strategy for inhibiting the hyperactivation of MCs by LPS over the course of allergic responses.

Direct oral anticoagulants versus vitamin K antagonists in epistaxis patients: A systematic review and meta-analysis.

OBJECTIVE: Epistaxis is the most common otolaryngological emergency and up to one third of patients in treated on an inpatient basis take oral anticoagulants (OAC). Direct oral anticoagulants (DOAC), an OAC subgroup, have been on the market since 2010 and are being increasingly prescribed due to the cardiological and haematological guidelines that favour them over vitamin K antagonists (VKA), the older of the OAC subgroups. The present study aims to investigate which subgroup of epistaxis patients taking OACs has a more favourable outcome. DESIGN/SETTING: A systematic review and meta-analysis were performed according to the PRISMA 2020 statement using the PubMed and Cochrane Library databases. Continuous data were analysed and standardised mean difference (SMD) was calculated according to Hedges' g. Dichotomous data were analysed, and the Mantel-Haenszel method was applied to establish the odds ratio (OR). Heterogeneity was assessed according to the I2  statistics. MAIN OUTCOME/RESULTS: A total of eight reports covering 1390 patients were included in the final synthesis. The pooled analysis demonstrated significantly shorter hospital stays in the DOAC group (SMD = -0.22, 95% CI-0.42 to -0.02, p = .03) and a significantly higher rate of posterior bleeding in the VKA group (OR = .39, 95% CI 0.23 to 0.68, p = .001). No statistically significant differences with regard to recurrence rates, admission rates, the need for transfusion or surgical intervention (p = .57, .12, .57 and .38 respectively) were found. CONCLUSION: According to this meta-analysis, epistaxis patients taking DOACs have a more favourable outcome than patients taking VKAs.

UV light-based reprocessing of flexible endoscopes without working channel in Oto-Rhino-Laryngology: an effective method?

BACKGROUND: Reprocessing of flexible endoscopes (FEs) is often expensive, time consuming, and becomes increasingly complex, due to rising demands of hygiene. After beneficial results in reprocessing of rigid endoscopes using Impelux™ UV-C light technology, we tested the same method for reprocessing of FEs without working channel. MATERIALS AND METHODS: Testing was performed on FEs without working channel after routine clinical use (transnasal flexible endoscopy). Disinfection consisted of mechanical precleaning and 60 s exposure to Impelux™ UV-C light technology. Bacterial contamination was tested on 50 FEs before and after disinfection. Further 50 FEs regarding protein residuals. The absolute effectiveness of the D60 was tested on 50 test bodies (RAMS) with a standardized contamination of 107 colony-forming units (CFU) of Enterococcus faecium. RESULTS: The FEs were contaminated with a high average value of 916.7 CFU (± 1057 CFU) after clinical usage. After reprocessing, an average contamination of 2.8 CFU (± 1.6) on 14% (n = 7) of the FEs was detected consisting of non-pathogenic species, the remaining FE were sterile. After reprocessing, all FEs were protein-free (< 1 µg). The artificially contaminated test bodies showed no remaining bacterial contamination after disinfection, resulting in an average absolute germ reduction of about 107 CFU. CONCLUSION: Impelux™ UV-C light technology efficiently reduces bacterial contamination of FEs and might be useful in daily practice.

Correction to: Safety of the "Saxophone®" electrode in parotid surgery for continuous intraoperative neuromonitoring of the facial nerve: results of a pro- and retrospective cohort study.

In the original publication of the article, first name and last names of all authors were swapped.

Safety of the "Saxophone®" electrode in parotid surgery for continuous intraoperative neuromonitoring of the facial nerve: results of a pro- and retrospective cohort study.

PURPOSE: Early facial nerve palsy (eFNP) is the most frequent complication of the parotidectomy. Intraoperative neuromonitoring (IONM) in parotid surgery, which aims at reducing eFNP, has not evolved any further than the mere differentiation between the nerve and the surrounding tissue. Continuous IONM (cIONM), used in thyroid and posterior fossa surgery, has developed over the past years and has proved beneficial in reducing the rate of paresis in cases where a pattern of impending nerve injury is identified. In this study, we aim to demonstrate the safety of using the stimulating electrode (Saxophone®) for cIONM in parotid surgery. METHODS: From 2016 to 2018, 40 patients who were referred for primary parotidectomy under cIONM according to our study protocol (registered at the German Clinical Trials Register, DRKS-ID: DRKS00011051, http://www.drks.de; http://apps.who.int/trialsearch) were included in this study. All patients with a normal preoperative facial nerve function [House-Brackman (HB)-Index 1] underwent surgery using continuous facial nerve stimulation with the Saxophone® electrode (system AVALANCHE XT, Dr. Langer Medical, Waldkirch, Germany). A control group which underwent parotidectomies with only intermittent IONM was recruited from our records. RESULTS: Half of the patients in our study group suffered from eFNP. All except one regained normal facial nerve function within 6 months of surgery. There was no significant difference regarding eFNP when compared to the control group without cIONM (p = 0.11). No statistically significant correlation between the stimulation threshold (p = 0.74) or the duration of nerve stimulation and eFNP was found (p = 0.51). CONCLUSION: We have demonstrated the safety of using the Saxophone®-electrode for cIONM of the facial nerve in parotid surgery. Future development of this method could enable the recognition of impending nerve injury and thus reduce eFNP.

Clinical relevance of CYFRA 21-1 as a tumour marker in patients with oropharyngeal squamous cell carcinoma.

BACKGROUND: The role of Cytokeratin fraction 21-1 (CYFRA 21-1) as a tumour marker for head and neck cancer is still a matter of research. The aim of the present study was to evaluate the clinical impact of CYFRA 21-1 for patients with oropharyngeal squamous cell carcinoma (OSCC). PATIENTS AND METHODS: Data of 180 patients with an initial diagnosis of OSCC of any stage between 2003 and 2017 were retrospectively analysed regarding the association between pretherapeutic CYFRA 21-1 levels, clinical characteristics, overall and disease-free survival. Additionally, the potential of CYFRA 21-1 for the detection of recurrent disease in the follow-up was evaluated. The cut-off value was set at 3.3 ng/ml. The median follow-up time was 2.85 years. RESULTS: A significant correlation of the CYFRA 21-1 concentration at the time of diagnosis and the N-stage was detected (p = 0.01). Patients with CYFRA 21-1 levels > 3.3 ng/ml at first diagnosis showed a significantly shorter overall survival. In the case of disease-progression, a significant increase of CYFRA 21-1 value was found compared to post-therapeutic CYFRA 21-1 levels (9.1 ng/ml versus 5.1 ng/ml; p < 0.01). CYFRA 21-1 level after treatment showed only a low sensitivity of 32% and a specificity of 78% for tumour recurrence. CONCLUSION: CYFRA 21-1 correlates with the tumour stage and, therefore, the survival of OSCC patients. Posttreatment CYFRA21-1 seems not to be a suitable predictor of tumour recurrence in the further course of the disease. However, a sudden increase of CYFRA 21-1 during follow-up may indicate a tumour recurrence in the individual patient.

UV light-based decontamination: an effective and fast way for disinfection of endoscopes in otorhinolaryngology?

BACKGROUND: Reprocessing of endoscopes becomes increasingly complex, due to rising demands of hygiene. Established methods are often expensive/time-consuming. Recent studies suggest beneficial aspects of disinfection by UV light. In this study we analyzed the efficiency of UV light disinfection of rigid otorhinolaryngological endoscopes. MATERIALS AND METHODS: After mechanical pre-cleaning, the endoscopes were decontaminated for 25 s in the D25 using Impelux™ UV C light technology (UV Smart B.V., Delft, The Netherlands). First, the surface contact samples were taken from 50 used endoscopes to evaluate the bacterial load. Additionally, surface contact samples were taken from further 50 used endoscopes after reprocessing with the D25. Another 50 endoscopes were tested on protein residuals. Furthermore, the absolute effectiveness of the D25 was tested on 50 test bodies (RAMS) with a standardized contamination of 107 colony-forming units (CFU) of Enterococcus faecium. RESULTS: The used endoscopes showed a high bacterial contamination with an average value of 66.908 (± 239.215) CFU. After reprocessing, only a minimal contamination on 10% (n = 5) of the endoscopes with a mean value of 0.12 CFU (± 0.39) was found, resulting in a log-5 reduction in a clinical environment. The documented bacteria were components of the normal skin flora. All tested endoscopes were practically protein-free (< 1 µg). Furthermore, the average absolute germ reduction of the D25 was about 106 CFU on the tested RAMS. CONCLUSION: The D25 UV light system seems to be an effective device for the reprocessing of rigid ORL endoscopes, and therefore, might be suitable for the usage in clinical practice on site.

Shorter hospital stays in epistaxis patients with atrial fibrillation when taking rivaroxaban or apixaban versus phenprocoumon.

Patients taking oral anticoagulants (OACs) currently represent one-third of all patients treated for epistaxis and an upward trend is expected. New direct oral anticoagulants (DOACs) have been on the market for approximately 10 years. DOACs are favoured over Vitamin K-Antagonists (VKAs) in the current guidelines. There are barely studies that investigate the impact of DOACs on patients with epistaxis. A retrospective study was performed analysing all patients who had stationary treatment for epistaxis from 01.01.2011 to 01.01.2018 in a tertiary care centre. In a total of 466 patients, 46.1% were on OACs. The main indication was atrial fibrillation (AF, 67.4%).The number of DOACs taken surpassed that of the VKAs during the past 2 years. The length of hospital stay was significantly longer in the phenprocoumon group (3 ± 0.2 days) in comparison to both the rivaroxaban (2.3 ± 0.1) and the apixaban (2.2 ± 0.1) groups (p = 0.005). Posterior epistaxis occurred more frequently in the phenprocoumon group (10.8%) than in the rivaroxaban (0%) and apixaban (0%) groups (p = 0.03). A correlation between CHA2DS2-VASc score (risk score for apoplexy in patients with AF, p = 0.01), HAS-BLED score (score for assessment of major bleeding in patients taking anticoagulants with AF, p = 0.006), and length of hospital stay (p = 0.002) with recurrence of epistaxis was found. Shorter hospital stays and exclusively anterior bleeding was noted in AF patients taking rivaroxaban and apixaban, whereas AF patients taking phenprocoumon stayed in hospital longer and had more posterior bleeding.

EPO and TMBIM3/GRINA Promote the Activation of the Adaptive Arm and Counteract the Terminal Arm of the Unfolded Protein Response after Murine Transient Cerebral Ischemia.

Ischemic stroke is known to cause the accumulation of misfolded proteins and loss of calcium homeostasis leading to impairment of endoplasmic reticulum (ER) function. The unfolded protein response (UPR) is an ER-located and cytoprotective pathway that aims to resolve ER stress. Transmembrane BAX inhibitor-1 motif-containing (TMBIM) protein family member TMBIM3/GRINA is highly expressed in the brain and mostly located at the ER membrane suppressing ER calcium release by inositol-1,4,5-trisphosphate receptors. GRINA confers neuroprotection and is regulated by erythropoietin (EPO) after murine cerebral ischemia. However, the role of GRINA and the impact of EPO treatment on the post-ischemic UPR have not been elucidated yet. We subjected GRINA-deficient (Grina-/-) and wildtype mice to transient (30 min) middle cerebral artery occlusion (tMCAo) followed by 6 h or 72 h of reperfusion. We administered EPO or saline 0, 24 and 48 h after tMCAo/sham surgery. Oxygen-glucose deprivation (OGD) and pharmacological stimulation of the UPR using Tunicamycin and Thapsigargin were carried out in primary murine cortical mixed cell cultures. Treatment with the PERK-inhibitor GSK-2606414, IRE1a-RNase-inhibitor STF-083010 and EPO was performed 1 h prior to either 1 h, 2 h or 3 h of OGD. We found earlier and larger infarct demarcations in Grina-/- mice compared to wildtype mice, which was accompanied by a worse neurological outcome and an abolishment of EPO-mediated neuroprotection after ischemic stroke. In addition, GRINA-deficiency increased apoptosis and the activation of the corresponding PERK arm of the UPR after stroke. EPO enhanced the post-ischemic activation of pro-survival IRE1a and counteracted the pro-apoptotic PERK branch of the UPR. Both EPO and the PERK-inhibitor GSK-2606414 reduced cell death and regulated Grina mRNA levels after OGD. In conclusion, GRINA plays a crucial role in post-ischemic UPR and the use of both GSK-2606414 and EPO might lead to neuroprotection.

Minimal residual disease in chronic lymphocytic leukemia: A consensus paper that presents the clinical impact of the presently available laboratory approaches.

Chronic lymphocytic leukemia (CLL) is a malignancy defined by the accumulation of mature lymphocytes in the lymphoid tissues, bone marrow, and blood. Therapy for CLL is guided according to the Rai and Binet staging systems. Nevertheless, state-of-the-art protocols in disease monitoring, diagnostics, and prognostics for CLL are based on the assessment of minimal residual disease (MRD). MRD is internationally considered to be the level of disease that can be detected by sensitive techniques and represents incomplete treatment and a probability of disease relapse. MRD detection has been continuously improved by the quick development of both flow cytometry and molecular biology technology, as well as by next-generation sequencing. Considering that MRD detection is moving more and more from research to clinical practice, where it can be an independent prognostic marker, in this paper, we present the methodologies by which MRD is evaluated, from translational research to clinical practice.

Exosome-carried microRNA-based signature as a cellular trigger for the evolution of chronic lymphocytic leukemia into Richter syndrome.

Even if considered a cumulative and not a proliferative CD5+ B-cell neoplasm, chronic lymphocytic leukemia (CLL) has a proliferation rate higher than that recognized earlier, especially in the lymphoid tissues. Some patients with CLL develop a clinical syndrome entitled Richter syndrome (RS). Understanding CLL genetics and epigenetics may help to elucidate the molecular basics of the clinical heterogeneity of this type of malignancy. In the present project we aimed to identify a microRNA species that can predict the evolution of therapy-resistant CLL towards RS. In the first phase of our study, microRNA-19b was identified as a possible target, and in the second phase, we transfected three different CLL cell lines with microRNA-19b mimic and inhibitor and assessed the potential role on leukemia cells in vitro. The mechanism by which miR-19b acts were identified as the upregulation of Ki67 and downregulation of p53. This was further supported through RT-PCR and western blotting on CLL cell lines, as well as by next generation sequencing on two patients diagnosed with CLL that evolved into RS.

Antero- vs. retrograde nerve dissection in parotidectomy: a systematic review and meta-analysis.

INTRODUCTION: The retrograde approach (RP) to nerve identification is a method seldom used in parotid surgery. A systematic review comparing this method to the standard anterograde approach (AP) with respect to facial nerve palsy (FNP) does not currently exist. METHODS: In a meta-analysis according to the PRISMA statement, eight publications, including one randomized controlled trial, were selected. The primary aim was to compare the temporary and permanent FNP resulting from the two dissection methods. Facial nerve function was graded according to the House-Brackmann Scale. The secondary goal was a comparison of the cut-suture times (CST), the volume of healthy tissue (VHT) dissected, the rates of postoperative hematoma (PH), and postoperative infection (PI). RESULTS: Temporary FNP was noted in 18.2% in the RP group as well as in 34.4% in the AP group. Permanent FNP occurred in 0.9% RPs and 2.4% APs. According to the mixed-effect logistic regression model, there was no significant difference between the two groups in the pooled odds ratio (OR) for either temporary [OR 2.64, 95% confidence interval (CI) 0.97-7.21] or permanent FNP (OR 4.31, 95% CI 0.44-42.28). The CST was significantly shorter in the RP group (p = 0.005), with a significantly smaller VHT dissected (p < 0.0001). There were no differences regarding PH and PI. CONCLUSION: The RP is a safe procedure with no significant difference in FNP rates when compared to the AP and, considering the shorter CST and the lesser VHT resected in the RP, it is superior to the AP. Surgeons engaged in parotidectomy should be familiar with both methods of dissection.

Super Natural II--a database of natural products.

Natural products play a significant role in drug discovery and development. Many topological pharmacophore patterns are common between natural products and commercial drugs. A better understanding of the specific physicochemical and structural features of natural products is important for corresponding drug development. Several encyclopedias of natural compounds have been composed, but the information remains scattered or not freely available. The first version of the Supernatural database containing ∼ 50,000 compounds was published in 2006 to face these challenges. Here we present a new, updated and expanded version of natural product database, Super Natural II (http://bioinformatics.charite.de/supernatural), comprising ∼ 326,000 molecules. It provides all corresponding 2D structures, the most important structural and physicochemical properties, the predicted toxicity class for ∼ 170,000 compounds and the vendor information for the vast majority of compounds. The new version allows a template-based search for similar compounds as well as a search for compound names, vendors, specific physical properties or any substructures. Super Natural II also provides information about the pathways associated with synthesis and degradation of the natural products, as well as their mechanism of action with respect to structurally similar drugs and their target proteins.

Visualization of anatomy in normal and pathologic middle ears by cone beam CT.

Cone beam computed tomography (CBCT, syn. digital volume tomography = DVT) was introduced into ENT imaging more than 10 years ago. The main focus was on imaging of the paranasal sinuses and traumatology of the mid face. In recent years, it has also been used in imaging of chronic ear diseases (especially in visualizing middle and inner ear implants), but an exact description of the advantages and limitations of visualizing precise anatomy in a relevant number of patients is still missing. The data sets of CBCT imaging of the middle and inner ear of 204 patients were analyzed regarding the visualization of 18 different anatomic structures. A three-step scale (excellent visible, partial visible, not visible) was taken. All analyses were performed by two surgeons experienced in otology and imaging. The indications for imaging were chronic middle ear disease or conductive hearing loss. Previously operated patients were excluded to rule out possible confounders. In dependence of a radiological pathology/opacity of the middle ear, two groups (with and without pathology) were built. Regarding the possibility of excellent visualization, significant differences were only found for small bony structures: incu-stapedial joint (25.8 vs. 63.5 %), long process of incus (42.7 vs. 88.8 %), head of stapes (27.0 vs. 62.6 %), anterior crus of stapes (16.9 vs. 40.9 %) and posterior crus of stapes (19.1 vs. 42.6 %). The other structures (semicircular canals, skull base at mastoid and middle ear, jugular bulb, sinus sigmoideus, facial nerve) could be visualized well in both groups with rates around 85-100 %. Even CBCT shows little limitations in visualization of the small structures of the middle and inner ear. Big bony structures can be visualized in normal as well as in pathologic ears. Overall, due to pathology of middle ear, an additional limitation of evaluation of the ossicular chain exists. In future, studies should focus on comparative evaluation of different diseases and different radiological modalities and be performed by radiologists and otologists together to improve the quality of reports and to answer clinical questions more satisfactorily.